Research Interests:

- Mitochondrial DNA replication in disease: AIDS, congestive heart failure, hepatitis, renal failure
One classic biological teaching is that mitochondria are the "powerhouses of the cell", particularly in tissues that require significant energy, like heart, liver and muscle. The focus of the Lewis lab is the diverse effects of toxins on mitochondria structure and function. The primary focus is the untoward mitochondrial effects of a class of drugs called nucleoside reverse transcriptase inhibitors (NRTI) used to treat HIV infection, that are known to inhibit mitochondrial (mt-) DNA replication in vitro. These drugs are toxic to various tissues including heart, skeletal muscle, liver and kidney. Our overall goals are to (1) define the molecular mechanisms of how NRTIs change the abundance of precursors for mtDNA replication in vivo (2) define the effects of active NRTI triphosphates on the mitochondrial replicon in vivo (3) define the effects of specific polymerase mutants on the replication of mtDNA in vivo and (4) define the effects of the mtDNA template itself on its replication in vivo. The approach taken employs tissue specific targeting of genes involved in the processes and evaluation of structural and functional defects that result using state of the art biochemical, molecular, physiological, and pathological approaches. Conditional, tissue specific targeting also is addressed. The direct clinical benefits of these studies are twofold (1) the toxicity of important compounds is defined so that better therapeutics can be designed and administered and (2) mechanisms of organ specific changes in HIV disease and related illnesses are elucidated.

Clinical Focus:

Cardiovascular Disease, Heart Transplantation, HIV effects on the cardiovascular system

Lewis, William "Pathologic changes in hearts of patients with AIDS in Cardiology in AIDS, S. Lipshultz, Editor; Chapman and Hall, New York

Lewis, William: "Mitochondrial toxicity of antiviral nucleosides used in AIDS: insights into mitochondrial cardiac and skeletal defects and changes in other tissues rich in mitochondria" in Cardiology in AIDS, S Lipshultz, Editor; Chapman and Hall, New York